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Newer approaches to treatment of disseminated disease

UNKNOWN PRIMARY TUMORS: NEWER CONCEPTS AND APPROACHES Rome, March 5-6, 2010. Newer approaches to treatment of disseminated disease. Matteo Landriscina, MD PhD Assistant Professor of Clinical Oncology University of Foggia. EPIDEMIOLOGY. CUP constitutes 2-4% of all malignacies

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Newer approaches to treatment of disseminated disease

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  1. UNKNOWN PRIMARY TUMORS: NEWER CONCEPTS AND APPROACHES Rome, March 5-6, 2010 Newer approaches to treatment of disseminateddisease Matteo Landriscina, MD PhD Assistant Professor of Clinical Oncology University of Foggia

  2. EPIDEMIOLOGY • CUP constitutes 2-4% of all malignacies • Annual age-adjusted incidence in US is 7-12 cases per 100,000 population • Median age at presentation is 60 years • Slightly more prevalent in males • 5-10% of case are characterized by a relatively favourable prognosis

  3. FAVORABLE SUBSETS • Women with isolated axillary adenopathy • Women with papillary serous adenocarcinoma of the peritoneal cavity • Squamous cell carcinoma involving cervical lymph nodes • Isolated inguinal adenopathy from squamous cell carcinoma • Men with bone metastases, elevated serum PSA, or PSA positive on tumor staining • Men with poorly differentiated carcinoma of midline distribution • Poorly differentiated neuroendocrine carcinoma • Single, small and potentially resectable metastatic site

  4. UNFAVOURABLE SUB-SETS • Adenocarcinoma metastatic to the liver or other organs • Non-papillary malignant ascites (adenocarcinoma) • Multiple cerebral metastases (adeno or squamous carcinoma) • Multiple lung/pleural metastases (adenocarcinoma) • Multiple metastatic bone disease (adenocarcinoma)

  5. TREATMENTUNFAVORABLE SUBSETS • With the exception of the favorable subsets, most patients with CUP have a tumor that is resistant to chemotherapy • The prognosis is very poor, with median survival of 2 to 3 months in unselected patients and 6 to 10 months in those enrolled into clinical trials • Patients with good performance status may benefit from systemic chemotherapy

  6. Chemotherapy for unfavorable subsetsOpen Questions • Which chemotherapy regimen? • Is the combination of Platinum and Taxane the standard of care? • Is there any role for a third agent?

  7. TREATMENTUNFAVORABLE SUBSETS

  8. TREATMENTUNFAVORABLE SUBSETS

  9. TREATMENTUNFAVORABLE SUBSETS

  10. TREATMENTUNFAVORABLE SUBSETS

  11. Randomized phase III comparison of paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan, both followed by gefitinib, in patients (pts) with carcinoma of unknown primary site (ASCO 2009, Abs 4931) • 198 pts were randomized to paclitaxel, carboplatin, etoposide (PCE, 93 pts) or gemcitabine, irinotecan (GI, 105 pts). Responding/stable pts then received gefitinib until tumor progression. • Median progression-free survival for PCE versus GI was 3.2 months versus 5.3 months, p=0.19 • Median overall survivals were 7.4 months (PCE) versus 8.6 months (GI), p=0.34 • 2-year survivals were 16% (PCE) and 19% (GI) • Response rates were similar (PCE 19%, GI 20%) • GI was less toxic, with lower rates of grade 3/4 neutropenia (11% vs. 35%; p< 0.01), febrile neutropenia (0% vs. 9%; p<0.01), thrombocytopenia (3% vs. 8%; p=.05), anemia (3% vs. 9%; p=0.05), and RBC transfusions (10% vs. 24%; p<0.01).

  12. CONCLUSIONS • Clinical trials evaluated a group of heterogeneous tumors sharing the unique characteristic of metastatic disease without identifiable origin at the time of initial therapy • Only phase II trials, few randomized • No randomized phase III trials designed to establish the efficacy of combination chemotherapy over BSC or Platinum single agent • Among unfavourable subsets, patients with good performance status may benefit from systemic chemotherapy • There is no chemotherapy of choice although the most commonly used regimens use the combination of a platinum and a taxane • The role for a third agent such as gemcitabine, irinotecan or etoposide remains unclear

  13. Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: Multiple-treatments meta-analysisGolfinopoulos et al, 2009 • Meta-analysis of 10 randomized controlled trials comparing at least two different systemic regimens or a systemic regimen to no treatment • Data on favorable subset CUP were excluded • Overall 683 subjects were randomly assigned • No trials compared systemic treatment to BSC

  14. Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: Multiple-treatments meta-analysisGolfinopoulos et al, 2009

  15. Multiple-treatment meta-analysis for deathGolfinopoulos et al, 2009

  16. Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: Multiple-treatments meta-analysisGolfinopoulos et al, 2009 • Multiple-treatments meta-analysis showed no significant benefit for any treatment group over others • No type of chemotherapy has been solidly proven to prolong survival in patients with CUP • Regimens using either platinum or taxanes or both show some trends for prolongation of survival, but the data a limited. Taxane regimens seem to have the best results • Median OS is 8-12 months for the trial published after the year 2000, but this gain may not necessary depend on systemic chemotherapy • A taxane/platimun combination may prolong survival by 1.5 months • BSC may be considered for old or unfit unfavorable CUP

  17. Open Issues • Molecular assignment of tissue of origin and response to chemotherapy • Molecular-targeted agents in unknown primary carcinomas • Liver metastases of unknown origin

  18. Autopsy-found primaries, N = 644 (%) Lung 27 Pancreas 24 Liver/bile duct 8 Kidney/adrenals 8 Bowel 7 Genital system 7 Stomach 6 Bladder/ureter 0.01 Breast 0.007 Other 10 DNA-assigned primaries, N > 500 (%) Lung 11.5 Pancreas 12.5 Liver/bile duct 8 Kidney/adrenals 6 Bowel 12 Genital system 9 Stomach 3 Bladder/ureter 5 Breast 15 Other 18

  19. Chemotherapy activity and patients outcome in CUP and metastatic tumors of known primary CUP-Platinum Advanced NSCLC N RR (%) MS (months) 918 32 9 5895 30-45 8-11 CUP-Anthra or GI Adv Pancreas Adv breast Adv colon N RR (%) MS (months) 401 22 7 4465 10-25 5-9 3953 40-70 18-24 13875 35-55 15-20

  20. Promising molecular targets and targeting compounds in CUP Molecule Ras HER2 EGFR C-KIT PDGFR BCL2 P53 VEGF VEGFR Therapeutic modulation Farnesyl-transferase inhibitors Antibodies, tyrosine kinase inhibitors Antibodies, tyrosine kinase inhibitors Tyrosine kinase inhibitors Tyrosine kinase inhibitors Antisense oligonucleotides Gene therapy, degradation inhibitors Antibodies Tyrosine kinase inhibitors Developed agents Tipifarnib, lonafarnib Trastuzumab, lapatinib Cetuximab, gefitinib, erlotinib Imatinib, sunitinib Imatinib, sunitinib Oblimersen G3139 ONYX015, INGN201, MI63 Bevacizumab ZD6474, sorafenib, sunitinib Pentheroudakis and Pavlidis, Cancer Treat Rev, 2006

  21. Method: IHC HER2 signalling in CUP Clinicopathologic parameters and outcome Author N Results Pavlidis, 1995 26 HER2 expression 65%, overexpression 27% None Hainsworth, 2000 100 HER2 overexpression 11% None Fizazi, 2003 56 HER2 overexpression 4% None Rashid, 2005 76 HER2 expression 68%, Overexpression 24% Co-expression of EGFR, HER2 and VEGF or Cox-2 in 54%. Superior survival on co-expession of EGFR, HER2 and Cox-2. Pentheroudakis and Pavlidis, Cancer Treat Rev, 2006

  22. Method: IHC, PCR, qPCR EGFR signalling in CUP Clinicopathologic parameters and outcome Author N Results Fizazi, 2003 56 EGFR overexpession 4% None Rashid, 2005 76 EGFR expression 75%, overexpression 61% Co-expression of EGFR, HER2 and VEGF or Cox-2 in 54%. Superior survival on coexpession of EGFR, HER2 and Cox-2 Dova, 2005 50 EGFR expression 74%, overexpression 12% Wild-type exons 18,19,21 EGFR gene in 96%. No exons 18, 19, 21 EGFR gene amplification None Pentheroudakis and Pavlidis, Cancer Treat Rev, 2006

  23. EGFR expression and response to chemotherapy Massard, Br J Cancer, 2007

  24. Method: IHC, PCR, qPCR cKIT signalling in CUP Clinicopathologic parameters and outcome Author N Results Fizazi, 2003 56 C-KIT overexpression 11% None Rashid, 2005 76 C-KIT expression 12%, overexpression 4% None Dova, 2005 50 C-KIT expression 81%, overexpression 13% No exon 11 C-KIT gene mutations None Pentheroudakis and Pavlidis, Cancer Treat Rev, 2006

  25. Method: IHC Angiogenesis in CUP (1) Clinicopathologic parameters and outcome Author N Results Van de Wouw, 2004 48 CD34 microvessel density median 56/mm3. VEGF expression 39%, overexpression 26% None Hillen, 1997 69 No difference in CD34 microvessel density between 39 CUP liver metastases and 30 known primary liver metastases CD34 microvessel density with adverse prognostic significance for survival Karavasilis, 2005 80 CD34 microvessel density median 59 microvessels/mm2 Positive correlation of VEGF with microvessel density. VEGF expression 100%, overexpression 83% Increased microvessel density in unfavourable group CUP Pentheroudakis and Pavlidis, Cancer Treat Rev, 2006

  26. Method: IHC Angiogenesis in CUP (2) Clinicopathologic parameters and outcome Author N Results Karavasilis, 2005 75 MMP2 expession 69%, overexpression 49% MMP9 expession 49%, overexpression 36% TIMP1 expession 79%, overexpression 44% Correlation of MMP2 and MMP9 expression. Adverse prognostic significance of TIMP1 expression Rashid, 2005 75 VEGF expression 49%, Overexpression 29% Co-expression of EGFR, HER2 and VEGF or Cox-2 in 54% Pentheroudakis and Pavlidis, Cancer Treat Rev, 2006

  27. Phase II trial which evaluated the combined inhibition of VEGF and EGFR with bevacizumab and erlotinib. • Patients who either had received previous chemotherapy or were previously untreated with poor-prognosis clinical features. • All patients received bevacizumab 10 mg/kg every 2 weeks, along with erlotinib 150 mg orally daily. • 47/51 patients received at least 8 weeks of treatment. • 10% PR, 61% SD • Median survival for the entire group was 7.4 months, with 33% of patients alive at 1 year. • This regimen was well tolerated by most patients.

  28. Hainsworth, J. D. et al. J Clin Oncol; 25:1747-1752 2007

  29. Hainsworth, J. D. et al. J Clin Oncol; 25:1747-1752 2007

  30. Phase II trial with thecombination of paclitaxel, carboplatin, bevacizumab, and erlotinibin the first-line treatment of patients with CUP • 49/60 patients completed 4 cycles of therapy,and 44 received maintenance bevacizumaband erlotinib. • 53% with major responsesto treatment; 18 patients with SD. • Median PFS was 8 months, with 38% of patients progression-free at 1 year. • Median survival 12.6 months; 2-year overallsurvival rate 27%. • Treatmentwas generally well tolerated.

  31. Liver Metastasis subgroup • CUPL is an unfavourable subset of cancer of unknown primary site • Male/female ratio 2:1. • Median age at diagnosis: 61–65. • Lung, pancreatic and colorectal primary tumors are most commonly identified in the setting of CUP patients presenting with liver metastases • The most commonly involved metastatic sites in addition to hepatic involvement are lymph nodes, bone and lung. • Adenocarcinoma is the prevalent histology (64%), followed by undifferentiated carcinoma (20%), neurondocrine (8.4%) and squamous (3%).

  32. Liver Metastasis subgroupResponse to chemotherapy Lazaridis et al, Cancer Tret Rev, 2008

  33. Liver Metastasis subgroup Lazaridis et al, Cancer Tret Rev, 2008

  34. Liver Metastasis subgroupPrognostic factors for OS Lazaridis et al, Cancer Tret Rev, 2008

  35. Liver Metastasis subgroupPrognostic Factors • Histology (neuroendocrine differentiation) • Liver Metastasis only/Number of metastatic sites • Age • Performance Status

  36. CONCLUSIONS • Potential roles for DNA microarray technology • Identify the primary site • Identify clinically relevant subsets of tumors with similar gene expression profiles • Identify specific and novel targets for treatment • Targeted therapies such as EGFR inhibitors and anti-angiogenesis agents may have a role in the treatment of CUP, particularly in patients with unfavorable subsets • PR 10%, SD 61% , Median survival 7.4 months in 2nd line • RR 53%, PFS 8 months, median survival 12.6 months in 1st line

  37. Current Clinical Practice Diagnosis of metastatic carcinoma Search for primary site AND Rule out non-carcinoma histology Lymphoma, melanoma, sarcoma Identify favorable subgroups Good PS Unfavorable subgroup BSC Poor PS ●Clinical trial ● Platinum-taxane chemotherapy

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